Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice.
Nutraceutical and pharmaceutical cocktails did not improve muscle function or reduce histological damage in D2-mdx mice.
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营养保健品和药物混合物不能改善 D2-mdx 小鼠的肌肉功能或减少组织学损伤。
DOI：
10.1152/japplphysiol.00162.2019
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Selsby,JoshuaT
中科院分区：
文献类型：
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作者：
Spaulding,HannahR;Quindry,Tiffany;Hammer,Kayleen;Quindry,JohnC;Selsby,JoshuaT
进行性肌肉损伤和无力是杜氏肌营养不良症的标志。我们以前表明，槲皮素（Q）部分保护营养不良的肢体肌肉免受疾病相关的损伤。由于槲皮素通过NAD+依赖性脱乙酰酶Sirtuin-1激活PGC-1α，营养不良骨骼肌中的NAD+耗尽可能会限制槲皮素的疗效;因此，补充NAD+供体烟酰胺核苷（NR）可能有助于槲皮素的疗效。赖诺普利（Lis）可保护肌营养不良蛋白缺陷小鼠的骨骼肌并改善心脏功能;因此，本研究纳入了赖诺普利与槲皮素和NR联合使用的效果。我们的目的是确定Q、NR和Lis减少营养不良性损伤的程度。我们假设Q、NR或Lis单独使用可改善肌肉功能并减少组织学损伤，当联合使用时会产生累加效应。在用Q、NR和/或Lis处理7个月后，评估11个月大的DBA（健康）、D2-mdx（肌营养不良蛋白缺陷）和D2-mdx小鼠的肌肉功能。为了模拟杜氏肌营养不良症患者的典型药理学，一组患者接受泼尼松龙（Pred）联合Q、NR和Lis治疗。在11个月的年龄，肌营养不良蛋白缺乏症的比目鱼肌和趾长伸肌的比张力和强直性肌力下降，并没有纠正任何治疗。营养不良的肌肉对收缩引起的损伤更敏感，这在QNRLisPred组中被部分抵消，而疲劳在所有组之间相似。治疗没有减少组织学损伤。这些数据表明用Q、NR、Lis和Pred治疗不能充分维持营养不良的肢体肌肉功能或减少组织学损伤。新&值得注意的是，尽管在短期研究中有令人信服的理由和以前的相反证据，但槲皮素、烟酰胺核苷或赖诺普利，单独或组合，在长期给药后，未能恢复肌肉功能或减少D2-mdx小鼠营养不良肢体肌肉的组织学损伤。重要的是，我们还发现，在D2-mdx模型中，一种新兴的和相对研究不足的杜氏肌营养不良症dystrophin缺乏症模型导致骨骼肌严重的肌肉功能障碍和组织病理学。
Progressive muscle injury and weakness are hallmarks of Duchenne muscular dystrophy. We showed previously that quercetin (Q) partially protected dystrophic limb muscles from disease-related injury. As quercetin activates PGC-1α through Sirtuin-1, an NAD+-dependent deacetylase, the depleted NAD+in dystrophic skeletal muscle may limit quercetin efficacy; hence, supplementation with the NAD+donor, nicotinamide riboside (NR), may facilitate quercetin efficacy. Lisinopril (Lis) protects skeletal muscle and improves cardiac function in dystrophin-deficient mice; therefore, it was included in this study to evaluate the effects of lisinopril used with quercetin and NR. Our purpose was to determine the extent to which Q, NR, and Lis decreased dystrophic injury. We hypothesized that Q, NR, or Lis alone would improve muscle function and decrease histological injury and when used in combination would have additive effects. Muscle function of 11-mo-old DBA (healthy), D2-mdx (dystrophin-deficient), and D2-mdx mice was assessed after treatment with Q, NR, and/or Lis for 7 mo. To mimic typical pharmacology of patients with Duchenne muscular dystrophy, a group was treated with prednisolone (Pred) in combination with Q, NR, and Lis. At 11 mo of age, dystrophin deficiency decreased specific tension and tetanic force in the soleus and extensor digitorum longus muscles and was not corrected by any treatment. Dystrophic muscle was more sensitive to contraction-induced injury, which was partially offset in the QNRLisPred group, whereas fatigue was similar between all groups. Treatments did not decrease histological damage. These data suggest that treatment with Q, NR, Lis, and Pred failed to adequately maintain dystrophic limb muscle function or decrease histological damage.NEW & NOTEWORTHYDespite a compelling rationale and previous evidence to the contrary in short-term investigations, quercetin, nicotinamide riboside, or Lisinopril, alone or in combination, failed to restore muscle function or decrease histological injury in dystrophic limb muscle from D2-mdx mice after long-term administration. Importantly, we also found that in the D2-mdx model, an emerging and relatively understudied model of Duchenne muscular dystrophy dystrophin deficiency caused profound muscle dysfunction and histopathology in skeletal muscle.